Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activity of N6-cycloalkyl derivatives of adenosine, 2-chloroadenosine, 5'-chloroadenosine and N-ethylcarboximidoadenosine (NECA) and of 2-fluoroadenosine and 5-methylthioadenosines were compared at the A1-adenosine receptor inhibitory to adenylate cyclase in rat fat cell membranes and at the A2A-adenosine receptors stimulatory to adenylate cyclase in rat PC12 cell membranes. The N6-cycloalkyl derivatives in all cases were more potent (4- to 23-fold) than the parent compound at the A1 receptor, and were less potent (1.6- to 11-fold) than the parent compound at the A2A receptor. N6-Cyclopentyl-5'-chloroadenosine was the most selective agonist (900-fold) for the A1 receptor, while 2-fluoroadenosine was the only agonist with some selectivity (4.8-fold) for the A2A receptor. 5'-Methylthioadenosine was a weak agonist at both adenosine receptors. A 2-fluoro derivative of 5'-methylthioadenosine was somewhat more potent. Affinities of these analogs for inhibition of binding of radioligands to rat brain A1 and A2A receptors are presented.
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PMID:Agonist activity of 2- and 5'-substituted adenosine analogs and their N6-cycloalkyl derivatives at A1- and A2-adenosine receptors coupled to adenylate cyclase. 155 81

Several lines of experimental evidence indicate the involvement of a guanine nucleotide-dependent protein (G-protein) in the hormone-stimulated hydrolysis of phosphatidylinositol(4,5)-bisphosphate (PtdIns(4,5)P2). However, the shortcomings of available procedures for cell-free assay of hormone-stimulated phosphoinositidase C (PIC) have limited our current understanding of the molecular and mechanistic details of PIC regulation. We recently have proposed that turkey erythrocyte membranes may provide a valuable model system for studies of G-protein-dependent PtdIns(4,5)P2 hydrolysis. The membranes can be simply prepared from [3H]inositol-labelled erythrocytes and they contain a PIC activity that hydrolyses endogenous phosphoinositides and is exquisitively sensitive to guanine nucleotides. PtdIns(4,5)P2 is the principal substrate for this enzyme, there being relatively little direct hydrolysis of phosphatidylinositol 4-phosphate and no detectable hydrolysis of PtdIns. The membranes also contain a purinoceptor of the P2y subclass that is efficiently coupled to PtdIns(4,5)P2 hydrolysis both in intact cells and in the isolated membranes. 2-Methylthioadenosine trisphosphate (2-methyl-S-ATP), a specific P2y receptor agonist, has no effect upon PtdIns(4,5)P2 hydrolysis in the absence of guanine nucleotides, but greatly enhances both the potency and efficacy of PIC activation by guanine nucleotides such as GTP gamma S. GTP gamma S alone stimulates PIC activity only after a prolonged time-lag; the effect of increasing doses of 2-methyl-S-ATP is progressively to shorten this lag phase. These results suggest that the mechanism of G-protein activation involves acceleration of a nucleotide exchange reaction as has been demonstrated for the activation of adenylate cyclase in the same membrane preparation. As well as contributing valuable information on the substrate specificity of PIC and its mode of regulation by hormones, turkey erythrocytes provide a plentiful source of plasma membranes and may be useful for purification of the appropriate G-protein and PIC activities.
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PMID:Receptor and G-protein-dependent regulation of turkey erythrocyte phosphoinositidase C. 290 38

The activities of an endogenous nucleoside, 5'-deoxy-5'-methylthioadenosine (MTA), on adenosine sensitive sites such as adenosine A1 and A2 receptors and the P-site, as well as on purine nucleoside transport, have been studied. This nucleoside competitively antagonized the A2 receptor-mediated stimulation of neuroblastoma adenylate cyclase, produced a GTP-dependent and 8-p-sulfophenyltheophylline-sensitive inhibition of adenylate cyclase activity in rat cerebellar membranes, and decreased the spontaneous contractile activity of isolated segments of rabbit jejunum. MTA was neither active at the P-site nor did it diminish the binding of [3H]nitrobenzylthioinosine, a nucleoside transport inhibitor. We conclude that (a) MTA is an agonist at the adenosine A1 receptor but an antagonist at the A2 receptor, and (b) the adenosine receptor which causes relaxation of rabbit jejunum is not a neuroblastoma-type A2 receptor which activates adenylate cyclase.
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PMID:5'-Deoxy-5'-methylthioadenosine: a nucleoside which differentiates between adenosine receptor types. 337 11

5'-Deoxy-5'-methylthioadenosine, a naturally occurring co-product of polyamine biosynthesis, has been shown to inhibit a variety of biological processes. To investigate the mode of action of this nucleoside and to assess the involvement of cAMP in this action, the effect of methylthioadenosine on S49 wild type and two cAMP-related mutant cells was examined. The sulfur-containing nucleoside potently inhibited the growth of the parental strain (IC50 = 50 microM), whereas nearly 10-fold greater resistance was demonstrated by S49 adenylate cyclase deficient (IC50 = 420 microM) and S49 cAMP-dependent protein kinase deficient (IC50 = 520 microM) mutant cells. Methylthioadenosine was shown to competitively inhibit the S49-derived high-affinity cAMP phosphodiesterase (Ki = 62 microM) in vitro, whereas methylthioadenosine phosphorylase activity was equivalent in all three cell types. The intracellular levels of the regulatory nucleotide, cAMP, increased dramatically in the wild type (17-fold) and protein kinase deficient (6-fold) strains in response to 100 microM concentrations of the drug. It is concluded that the growth arrest produced by 5'-methylthioadenosine in S49 cells is primarily due to the inhibition of cAMP phosphodiesterase and the subsequent increase in cAMP levels that result.
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PMID:Mechanism of action of 5'-methylthioadenosine in S49 cells. 609 57

Membranes from rat cerebral cortex and striatum contain a relatively large number of high-affinity binding sites for [3H]2',5'-dideoxyadenosine, [3H]adenine arabinoside, and [3H]adenosine. The binding of [3H]2',5'-dideoxyadenosine and [3H]adenine arabinoside was virtually unaffected by relatively specific agonists and antagonists for adenosine receptors, such as 2-chloroadenosine, N6-phenylisopropyladenosine or theophylline. Binding of [3H]adenosine was partially blocked by such receptor ligands. The specific binding of all three ligands was antagonized by a variety of adenosine analogs which inhibit adenylate cyclase by interaction with the so-called P-site associated with this enzyme. However, potencies of adenosine analogs as P-site inhibitors of adenylate cyclase and as antagonists of binding do not correlate well. 5'-Methylthioadenosine had high potency and efficacy versus binding of [3H]2',5'-dideoxyadenosine but had virtually no effect on activity of adenylate cyclase. 2-Fluoroadenosine was less potent than adenosine as an antagonist of specific binding of [3H]2',5'-dideoxyadenosine, while 2-fluoroderivatives of adenosine, adenine arabinoside and adenine xylofuranoside were more potent than the parent compounds as P-site inhibitors. The significance of the binding sites for [3H]2',5'-dideoxyadenosine remains unclear, but their presence complicates the use of [3H]adenosine and certain analogs as ligands for adenosine membrane sites associated with adenylate cyclase.
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PMID:Binding of 2',5'-dideoxyadenosine to brain membranes. Comparison to P-site inhibition of adenylate cyclase. 698 53

Hot water extracts of Mo-er (1 gm by 15 ml of water), an oriental food (Auricularia auricula), inhibit strongly both human and rat platelet ADP-induced aggregation. HPLC analysis of two varieties of Mo-er, A. auricula and A. polytricha (a black tree fungus), shows that they contain adenosine (Ado), 133 and 154 micrograms per gram of dry fungus, respectively. The inhibition of ADP-induced platelet aggregation by Mo-er extracts and by Ado was compared. Mo-er extracts caused a more rapid onset and a longer duration of inhibition that produced by equivalent amounts of Ado. Furthermore, Mo-er extract treated with adenosine deaminase to degrade the Ado retained the capacity to inhibit platelet aggregation. The inhibitory effects of Mo-er extracts of ADP-induced human platelet aggregation are greatly potentiated by the inhibitors of cyclic AMP phosphodiesterase such as oxagrelate (phthalazinol) and papaverine. The inhibition of platelet aggregation is only partially blocked by 2',5'-dideoxy-adenosine (DDA), an inhibitor of platelet adenylate cyclase and 5'-deoxy, 5'-methylthioadenosine (MTA), an antagonist of ADO receptors. ADP-induced rat platelet aggregation is strongly inhibited by Mo-er extracts, but not by Ado. This inhibition is not reversed by either DDA or MTA. These findings indicate that Mo-er extracts contain an agent (or agents) in addition to Ado, that blocks platelet aggregation by a mechanism that does not involve the platelet cyclic AMP system.
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PMID:Inhibition of human and rat platelet aggregation by extracts of Mo-er (Auricularia auricula). 698 40

In common with many other animal cells in culture, BHK21, CHO and NIH-3T3 cells adopt bizarre stellate or arborized shapes when exposed, in the absence of serum, to agents which increase cytoplasmic cyclic AMP (cAMP). Dibutyryl cAMP, 3-isobutyl-1-methylxanthine, 5'-deoxy-5'-methylthioadenosine, cholera toxin and the invasive adenylate cyclase from Bordetella pertussis all induce similar shapes. Time lapse video recording of BHK21 cells spreading on fibronectin shows that stellate shapes are generated by outgrowth of neurite-like processes led by small fans of ruffling membrane. These structures stain strongly for F actin, and their outgrowth is completely inhibited by cytochalasin D. Thus if stellation is caused by microfilament depletion, this must be selective for subsets of microfilaments. We have quantified the shape changes of BHK21 cells using the parameter dispersion. They are prevented by low concentrations (1% by volume and below) of bovine sera. The inhibitory component of foetal bovine serum acts humorally, behaves as a macromolecule and is itself inhibited by suramin, but platelet-derived growth factor, insulin, vasopressin and bradykinin are inactive. The inhibitory activity of serum may be due to phospholipids, since it can be replaced by lysophosphatidic acid in the presence of serum albumin.
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PMID:Shapes of cells spreading on fibronectin: measurement of the stellation of BHK21 cells induced by raising cyclic AMP, and of its reversal by serum and lysophosphatidic acid. 838 76